Project Summary: My career goal as an independent scientist is to understand the cellular and molecular processes involved in axon elongation and pathfinding and to identify the role of these processes in neurodevelopmental and mental health disorders. During my postdoctoral training in the laboratory of Dr. Samie R. Jaffrey at Weill Medical College of Cornell University, I have studied the role of intra-axonal mRNA translation and protein degradation. This training complements my doctoral training in protein biochemistry and synaptic plasticity. I plan to combine in vitro studies in primary neurons with mouse genetics to study the signaling pathways governing axonal pathfinding. The objective of this research is to examine to role of local protein translation and degradation in netrin-1 signaling. I have found that the PAR complex is a critical effector of netrin-1 signaling, and that the transcript encoding PAR3, a central component of the PAR complex, is localized to axons and translated in response to netrin-1. Based on my preliminary data, I propose three aims. First, I will characterize the role of a PAR complex effector, the ubiquitin E3-ligase Smurfl, in netrin-1-mediated axon elongation and growth cone turning. Second, I will use a fluorescent reporter of PARS translation and axon-specific RNA interference to address the role of local PAR3 translation in netrin-1 signaling. For these studies, I will develop new techniques to study growth cone turning to complement existing ones for the study of axon growth. Third, this application describes the design, generation, and analysis of transgenic mice that exhibit conditional localization of the PAR3 transcript to axons. These mice will allow the physiological role of axonal PARS translation to be established in axonal pathfinding. This research will significantly advance our understanding of netrin-1 signaling, and it will provide training in cellular, molecular, and genetic approaches to neuroscience. Relevance: During development, guidance molecules in the immature brain direct axons to their target areas, following long and complex pathways; disturbances in this process cause neurodevelopmental disorders, such as schizophrenia. This application seeks to explain the mechanisms inside an axon causing it to grow towards or away from guidance molecules. I expect that my studies will have broad relevance and might identify possible targets for the treatment or prevention of neurodevelopmental disorders. [unreadable] [unreadable] [unreadable]